For instance, take morphine. It is used as a baseline for measuring the potency of opioid agonists. Its structure looks like this:
6-Monoacetylmorphine is around 30% more potent than heroin itself:
If, however, the acetyl group is bonded to the top instead of the bottom, the resulting substance is less active than heroin. U-47700, a research chemical, has a totally different structure but has around 7.5 times the potency of morphine in animal models:
Desomorphine is 8-10 times more potent as morphine:
Oxymorphone is 10 times as potent as morphine:
The common explanation that I've heard for these substances being potent opioid agonists is that they mimic the endorphins produced in the human brain. However, Beta-Endorphin is 18-33 times more potent than morphine, and its structure is thus:
That looks absolutely nothing like any of the substances mentioned above. How can molecules with structures so radically different from those of endorphins mimic the action of endorphins? And how come U-47700 has a potency similar to the more powerful morphine analogues but looks nothing like them?
But then, there's Fentanyl:
100 times more potent than morphine, making it a more powerful Opioid receptor agonist than the body's own endorphins, and its structure looks nothing like them or any of the other ones so far. Other analogues are even more potent. So what is it about a molecule's structure that makes it a potent opioid? The only structural similarity that I can spot is the presence of a tertiary amine group in the structure. And how does U-47700 have a potency similar to the more powerful morphine analogues?